The Journal of Experimental Medicine
IN Cell Analyzer 2000
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© The Rockefeller University Press, 0022-1007/1999/6/1685/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 11, June 7, 1999 1685-1690

Articles

Early Induction of Cyclin D2 Expression in Phorbol Ester–responsive B-1 Lymphocytes

Debra A. Tanguay*, Thomas P. Colarusso{ddagger},||, Sandra Pavlovic*, Macarena Irigoyen{ddagger},||, Robert G. Howard{ddagger},||, Jiri Bartek, Thomas C. Chiles*, and Thomas L. Rothstein{ddagger},§,||

From the * Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467; the {ddagger} Department of Medicine, the § Department of Microbiology, and || The Evans Memorial Department of Clinical Research, Boston University Medical Center, Boston, Massachusetts 02118; and the Division of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark DK-2100

B-1 lymphocytes represent a distinct B cell subset with characteristic features that include self-renewing capacity and unusual mitogenic responses. B-1 cells differ from conventional B cells in terms of the consequences of phorbol ester treatment: B-1 cells rapidly enter S phase in response to phorbol ester alone, whereas B-2 cells require a calcium ionophore in addition to phorbol ester to trigger cell cycle progression. To address the mechanism underlying the varied proliferative responses of B-1 and B-2 cells, we evaluated the expression and activity of the G1 cell cycle regulator, cyclin D2, and its associated cyclin-dependent kinases (Cdks). Cyclin D2 expression was upregulated rapidly, within 2–4 h, in phorbol ester–stimulated B-1 cells, in a manner dependent on intact transcription/translation, but was not increased in phorbol ester– stimulated B-2 cells. Phorbol ester–stimulated cyclin D2 expression was accompanied by the formation of cyclin D2–Cdk4, and, to a lesser extent, cyclin D2–Cdk6, complexes; cyclin D2– containing complexes were found to be catalytically functional, in terms of their ability to phosphorylate exogenous Rb in vitro and to specifically phosphorylate endogenous Rb on serine780 in vivo. These results strongly suggest that the rapid induction of cyclin D2 by a normally nonmitogenic phorbol ester stimulus is responsible for B-1 cell progression through G1 phase. The ease and rapidity with which cyclin D2 responds in B-1 cells may contribute to the proliferative features of this subset.

Key Words: B lymphocytes • B-1 cells • B-2 cells • cyclins • cyclin-dependent kinases

Address correspondence to Thomas L. Rothstein, Boston Medical Center, Rm. E-556, 88 East Newton St., Boston, MA 02118. Phone: 617-638-7028; Fax: 617-638-7530; E-mail: trothstein{at}med-med1.bu.edu

D.A. Tanguay's present address is Department of Microbiology, Boston University School of Medicine, 80 East Concord St., Boston, MA 02118.

Abbreviations used: Cdk, cyclin-dependent kinase; DTT, dithiothreitol; GAPDH, glyceraldehyde-6-phosphate dehydrogenase; sIg, surface immunoglobulin; STAT, signal transducer and activator of transcription.


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